Brett Haumann

Evaluation of an ambulatory system for the quantification of cough frequency in patients with chronic obstructive pulmonary disease

BackgroundTo date, methods used to assess cough have been primarily subjective, and only broadly reflect the impact of chronic cough and/or chronic cough therapies on quality of life. Objective assessment of cough has been attempted, but early techniques were neither ambulatory nor feasible for long-term data collection. We evaluated a novel ambulatory cardio-respiratory monitoring system with an integrated unidirectional, contact microphone, and report here the results from a study of patients with COPD who were videotaped in a quasi-controlled environment for 24 continuous hours while wearing the ambulatory system.MethodsEight patients with a documented history of COPD with ten or more years of smoking (6 women; age 57.4 ± 11.8 yrs.; percent predicted FEV1 49.6 ± 13.7%) who complained of cough were evaluated in a clinical research unit equipped with video and sound recording capabilities. All patients wore the LifeShirt® system (LS) while undergoing simultaneous video (with sound) surveillance. Video data were visually inspected and annotated to indicate all cough events. Raw physiologic data records were visually inspected by technicians who remained blinded to the video data. Cough events from LS were analyzed quantitatively with a specialized software algorithm to identify cough. The output of the software algorithm was compared to video records on a per event basis in order to determine the validity of the LS system to detect cough in COPD patients.ResultsVideo surveillance identified a total of 3,645 coughs, while LS identified 3,363 coughs during the same period. The median cough rate per patient was 21.3 coughs·hr-1 (Range: 10.1 cghs·hr-1 – 59.9 cghs·hr-1). The overall accuracy of the LS system was 99.0%. Overall sensitivity and specificity of LS, when compared to video surveillance, were 0.781 and 0.996, respectively, while positive- and negative-predictive values were 0.846 and 0.994. There was very good agreement between the LS system and video (kappa = 0.807).ConclusionThe LS system demonstrated a high level of accuracy and agreement when compared to video surveillance for the measurement of cough in patients with COPD.

The Efficacy and Safety of the Novel Long-Acting β2 Agonist Vilanterol in Patients With COPD: A Randomized Placebo-Controlled Trial

BACKGROUND Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. METHODS Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. RESULTS VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. CONCLUSIONS VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.

Fluticasone furoate demonstrates efficacy in patients with asthma symptomatic on medium doses of inhaled corticosteroid therapy: an 8-week, randomised, placebo-controlled trial

Background Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24 h activity. FF is being developed as a once-daily treatment in combination with the long-acting β2 agonist vilanterol trifenatate for asthma and chronic obstructive pulmonary disease. Objectives To determine the optimal dose(s) of FF for treating patients with asthma. Methods An 8-week multicentre, randomised, double-blind study. 627 patients with persistent moderate-to-severe asthma, symptomatic on medium-dose inhaled corticosteroid therapy, were randomised to placebo, FF 200, 400, 600 or 800 μg (once daily in the evening using a novel dry powder inhaler), or fluticasone propionate 500 μg twice daily (via Diskus™/Accuhaler™). The primary efficacy measure was mean change from baseline in pre-dose evening forced expiratory volume in one second (FEV1). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom-free 24 h periods. Results Each dose was significantly superior to placebo for the primary endpoint (p<0.001) with efficacy at least similar to that reported with fluticasone propionate. There was no dose–response relationship across the FF doses studied. Peak expiratory flow improved in all groups (p<0.001 vs placebo), and there were significant treatment effects on rescue/symptom-free 24 h periods with all active treatments. FF was generally well tolerated. The incidence of oral candidiasis was higher with FF 800 μg than placebo; pharmacokinetic and 24 h urinary cortisol analyses confirmed a higher systemic exposure of FF at this highest dose level. Conclusions FF doses <800 μg have a favourable therapeutic index. The absence of an efficacy dose response suggests that 200 μg is an appropriate dose in patients with moderate persistent asthma. ClinicalTrials.gov identifier NCT00603746.

24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids

Current guidelines recommend adding a long-acting inhaled &bgr;2-agonist (LABA) to inhaled corticosteroids (ICS) in patients with uncontrolled asthma. This study evaluated the novel, once-daily LABA vilanterol trifenatate (VI) in asthma patients who remained symptomatic despite existing ICS therapy. The study involved a randomised, double-blind, placebo-controlled trial of VI (3, 6.25, 12.5, 25 and 50 μg), administered once daily in the evening by dry powder inhaler for 28 days, in asthma patients aged ≥12 yrs symptomatic on current ICS therapy. The primary end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV1); secondary end-points were weighted mean FEV1, peak expiratory flow (PEF), symptom-/rescue-free 24-h periods, and safety. A significant relationship was observed between VI dose and improvements in trough FEV1 (p=0.037). Statistically significant increases in mean trough FEV1, relative to placebo, were documented for VI 12.5–50 μg (121–162 mL; p≤0.016). Dose-related effects of VI were observed on weighted mean (0–24 h) FEV1, morning/evening PEF, and symptom-/rescue-free 24-h periods. All doses of VI were well tolerated with low incidences of recognised LABA-related adverse events (tremor 0–2%; palpitations 0–2%; glucose effects 0–1%; potassium effects 0–<1%). Once-daily VI 12.5–50 μg resulted in prolonged bronchodilation of at least 24 h with good tolerability in asthma patients receiving ICS. Based on the overall efficacy and adverse event profile from this study, the optimum dose of VI appears to be 25 μg.

Efficacy and safety of 4 weeks' treatment with combined fluticasone furoate/vilanterol in a single inhaler given once daily in COPD: a placebo-controlled randomised trial

Background Fluticasone furoate/vilanterol (FF/VI) is a novel once-daily (OD) inhaled corticosteroid/long-acting β2 agonist combination in development for chronic obstructive pulmonary disease (COPD) and asthma. Trial design A multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Methods Participants were patients with moderate-to-severe COPD treated with placebo or FF/VI 400/25 μg OD for 4 weeks. Study objectives were to assess the safety and efficacy of FF/VI 400/25 μg OD administered for 4 weeks via a novel dry powder inhaler. Co-primary end points were change from baseline in weighted mean (wm) heart rate 0–4 h postdose at day 28 and the incidence of adverse events (AEs). Secondary end points included change from baseline in trough forced expiratory volume in one second (FEV1) (23–24 h postdose; day 29) and wm FEV1 (0–4 h postdose; day 28). Patients were randomised to receive FF/VI 400/25 μg or placebo in a 2:1 ratio; all patients and investigators were blinded to active or placebo treatment. Results 60 patients (mean age 64 years) were randomised (FF/VI: n=40; placebo: n=20), and all contributed data to the analysis. Mean screening post-bronchodilator FEV1 per cent predicted was comparable between groups (FF/VI: 58.5%; placebo: 60.1%). The wm heart rate 0–4 h postdose was similar between groups (difference: 0.6 beats per minute; 95% CI −3.9 to 5.1). More on-treatment AEs were reported in the FF/VI group (68%) compared with the placebo group (50%). The most common drug-related AEs in the FF/VI group were oral candidiasis (8%) and dysphonia (5%). There were no clinically relevant effects on laboratory values, including glucose and potassium, or on vital signs or ECGs/Holters. The FF/VI group had statistically greater improvements compared with placebo in trough FEV1 (mean difference 183 ml) and 0–4 h postdose wm FEV1 (mean difference 236 ml). Conclusion FF/VI has a good safety and tolerability profile and improves lung function compared with placebo in patients with COPD. Trial registration number clinical trials.gov—NCT00731822.

Once-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroids

BACKGROUND Fluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma. OBJECTIVE To assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 μg/day or equivalent). METHODS This double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV1) at week 8. RESULTS At week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV1. There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo. CONCLUSION FF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00603278.

Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma

BackgroundInhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients.MethodsPatients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed.ResultsThe intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02).ConclusionsFF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.Trial registrationClinicaltrials.gov; NCT00766090.

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial

BackgroundFluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.MethodsAsthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV1) 50-80% of predicted normal value and FEV1 reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV1 at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV1.ResultsA total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV1 compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV1 at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV1 than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.ConclusionsFF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.Trial registrationNCT00398645

Efficacy and optimal dosing interval of the long-acting beta2 agonist, vilanterol, in persistent asthma: A randomised trial

BACKGROUND Vilanterol (VI) is a novel once-daily long-acting beta₂ agonist with inherent 24-h activity. The aim of this study was to evaluate the efficacy of three once-daily doses and one twice-daily dose of VI used concurrently with ICS in adult patients (≥18 years) with persistent asthma. Safety was also assessed. METHODS Multicentre, randomised, double-blind, placebo-controlled, five-period crossover study consisting of 7-day treatment periods separated by 7-day wash-out periods. Seventy-five patients, maintained on ICS, received VI 6.25, 12.5 and 25 mcg once-daily (evening), VI 6.25 mcg twice-daily (morning/evening), and placebo. The primary endpoint was trough forced expiratory volume in 1 s (FEV(1)) (mean of 23 h and 24 h post evening dose) on Day 7; secondary endpoint was weighted mean 24-h serial FEV(1) on Day 7. RESULTS All VI groups demonstrated statistically significant increases in trough FEV(1) versus placebo (p < 0.001). There was a statistically significant increase in weighted mean 24-h FEV(1) for each VI group versus placebo (p < 0.001). The effects of once-daily VI on trough FEV(1) and weighted mean 24-h FEV(1) were dose dependent. The incidence of adverse events (AEs) was low in each VI treatment group and was not dose dependent (5-9%; placebo = 18%); no drug-related AEs or serious AEs were reported. CONCLUSION Once-daily treatment with VI was well tolerated and associated with improvements in lung function. The VI 6.25 mcg twice-daily dose showed the greatest change in trough FEV(1), however, similar changes in weighted mean 24-h FEV(1) with VI 12.5 mcg once-daily were observed. Although our study was not powered to demonstrate non-inferiority of once- versus twice-daily dosing of VI, the data suggest no advantage over a 24-h period of twice-daily over once-daily dosing for the same total daily dose. ClinicalTrials.gov: NCT00980200.